MX2010013842A - Naphthyridininones as aurora kinase inhibitors. - Google Patents

Abstract

Naphthyridinone derivative compounds that inhibit Aurora kinase enzymes are disclosed along with pharmaceutical compositions comprising these compounds and methods for synthesizing the same. Such compounds have utility in the treatment of proliferative diseases resulting from unregulated and/or disturbed Aurora kinases such as cancers, psoriasis, viral and bacterial infections, inflammatory and autoimmune diseases.

Description

NA TIRIDINONES AS INHIBITORS OF AURORA CINA Field of the Invention The present invention relates to iridinone comp and its use as pharmacological agents capable of inhibiting particular protein kinases and auror, which inhibit abnormal proliferation and er lar.

Background of the Invention Protein kinases represent a graotein, which plays a central role in the wide variety of cellular processes, and for control over cellular function. These are Akt, Axl, Aurora A, Aurora B, Aurora Q 2, fgfr3, flt-3, vegfr3, igflr, IKK2, JNK3, Vegf autoimmune, inflammatory, cardiovascular, myeloproliferative and neurodegenerative diseases and asthma, Alzheimer's disease and enf cionadas with hormones. Accordingly, there has been substantial erratum in medicinal chemistry for protein kinase binders that are therapeutic effects.

Compounds of the present invention novel competitive, selective and other Aurora kinases (A, B and C). The conserved na / threonine kinases family perform during cell division. The three pairs are very similar in sequence, but only in their location, function, their regulatory jas.

Aurora A is mainly associated with mático and exit from metaphase I. Regulation occurs through phosphorylation / defosphorylation. Protein phosphatase 1 regulates nega ra A and this interaction is modulated by TPX2.

Aurora B is a chromosome-pas protein multiple functions in mitosis. The core protein (INCENP) and survivin, another two passenger components, function as dir.dor factors for the kinase (Bishop JD and Shumache, Chem. (2002) 277: 27577-27580). Aurora B will phosphorylate histone H3, direct the count to normal chromosomes. It is also understood that it is essential for osteo biorientació, kinetocor-microtubule interactions and splicing of the achromatic spindle assembly. The signal to complete the cytokinesis. s of cancers, which include cancers of colon s cancers of solid tumors. The genes that Aurora A and B kinases tend to be amplifi ed types of cancers, while the gene that Aurora C kinase lies in a region of the chromosome subject to realignment and deletion. The Aurora has been associated with a variety of malignancies, which are primary colon, colorectal, breast, io, prostate and cervical, neuroblastoma, and other solid tumors (Warner et al. (2003) Molecular apeutics 2: 589-95). Since Aurora A and frequently elevated or overexpressed in us, makes them attractive targets for therapy (Mountzios et al., Cancer Treatment 8) 34: 175-82; Gautschi et al., Clin. Cancer Res) .1639-48; Mortlock et al., Current Topics in a deep inhibition of tumor growth age of xenograft models in vivo, what leukemia strain, tolerated colon and pancreatic tumors (Harrington et al., Nat. Med., (2004). Novel cell cycle inhibitor, JNJ tra potent inhibition of several kinase dependent ina (CDKs) and Aurora kinases, and blocks selectivity of tumor cells from several low-entry sites, JNJ-7706621 decelerates the er cells at high toxicity concentrations. of cells with JNJ-7 exhibited a delayed progression through Gl lar and a cell cycle arrest in F Nuel et al., Cancer Res., (2005) 65: 9038-9046). Additional strains due to inhibition include endoreduplication and inhibition. Cyanamid Company discovered certain cyano-substituted deridine derivatives that are sa inhibitors, and therefore are effective age inhibitors of human tumor cell lines such as the SKB R3 cell line. (WO 2000/06658 Accordingly, an object of the invention is to provide naphthyridine compounds which have altered Aurora kinase activity.

Another object of the present invention is pharmaceutical possessions either individually or it, and methods for using same to treat tumors, such as cancers, psoriasis, in and bacterial, vascular restenosis, inflammatory and autoimmune, which result from prolific not regulated and not controlled.

Summary of the Invention The present invention relates to computation, regulating and / or modulating the transduction of protein kinases, such as A 2, epha2, fgfr3, flt-3, vegfr3, igflr, IKK r2, MEK1, MET, P70s6K, Plkl , RSK1 # Src, TrkA, bRaf, EGFR, Jak2, PI3K, NPM-Alk, c-Abl,? Rf TAK1, LimKf Flt3, Fltl, PDK1 and Erk, and espe the Aurora kinases A, B and C. The invention relates to compositions comprising these compounds for using the compounds in the treatment and conditions related to Auror a first aspect. , the present invention has a structure according to I: R R is H, halogen, cyano, nitro, luoromethyl, heteroalkyl, OR ", SR 'and NR'R", in R "each independently is H, genoalkyl, alkylohalogen, or heteroalkyl, na heteroalkyl which optionally binds in emo to attached carbon atoms of the ring is attached, whereby a cyclic structure is formed; Ri, R2, R3, each independently is ether or oxidized form of sulfur such as an onyl, sulfanyl, sulfinimide, or sulfonamide; or, amino, alkyl, formyl, hydroxy, hydroxy X, cyano, carboxy, carboxylic acid, an oxyl ester, a carboxylic acid amide such as Ry), acetic acid, acetic acid, or acetic acid ester including an acid amide acé pendiense can be H, oalkyl, dialkylaminoalkyl, oalkyl, carbocycloalkylamino, or het oalkyl; and wherein the two groups one or N of an aminoalkyl group, together or N to which they are attached, can bind a heterocyclyl group; n is 1, 2, 3 or 4, with the condition of being = 0 when X is other than oxygen a salt, prodrug, hydrate, ore, enantiomer or mixture Acceptically acceptable thereof.

In a preferred embodiment, the computer with the formula I is incorporated pharmaceutical ulation together with one agent, excipient, vehicle, (?) where: X is NH, NH-CH2, NH-C (= 0) / (-C = 0) NH, NH-C (02NH, CH2, -C = C-, -CH = CH, or a heterocycle; And and W each independently is O, S or A is a 3-7 membered ring, saturated, optionally having 1 or more heterons optionally substituted; Cy is selected from the group consisting of unsubstituted or substituted alkyl, bicycloal 0) -N (R x R y), substituted or unsubstituted aryl, heterocyclic or substituted heteroaryl, alkylamino, dialkylamino, alkylamino-lanylaminoalkyl, alkyldiamino, alkylamyldiaminoalkoxy, heterocyclic alkoxy, dialkylammoxyalkyl-hydroxycarboxylic acid alkylamide, hydroxy ester -alkylamide dihydroxy-alkylamide, acetic acid oxyalkylamide; wherein R x and R y c may independently be H, alkyl, aminalkylaminoalkyl, arylaminoalkyl, caalkyl, or heteroaryl-aminoalkyl; and wherein the N atom of an aminoalkyl group attached to the N atom to which they are attached, can bind a heterocyclyl group; or a salt, prodrug, hydrate, solvate, t where : X is NH, NH-C (= 0), NH-CH2,. { -C = 0) NH, NH-C. { 02NH, CH2 / -C = C-, O -HC = CH-; Q is NH (C = Y) or (C = Y) NH; And and W each independently is O, S Z 'is CH or N; A is a 3-7 membered ring, saturated, optionally having 1 or more heteromethyl, a carboxylic acid amide such as Ry), acetic acid, acetic acid, or acetic acid ester which includes an acid acide amide. substitutions - (C = 0) -N (RxRy), substituted aryl, heterocyclic alkoxy, heterocycle or heterocycle or unsubstituted, alkylamino, dialkylaminoalkyl, dialkylaminoalkyl, alkylaminoalkoxy, alkyldiaminoalkoxy, alkoxy heterylaminoamide, carboxylaminoamide , hydroxyalkyl-hydroxy, ilamide ester, dihydroxy-alkyloxyalkylamide-acetic acid ester, wherein R x and R y can independently be H, alkyl, amino quilaminoalkyl, arylaminoalkyl, cakalkyl, or heteroaryl-aminoalkyl; and where you are linked to the N atom of an aminoalkyl group In a fourth aspect of the present invention a compound of the general formula IV, where: X is NH, NH-C (= 0), NHCH2, (-C = 0) NH, NH-C (= 02NH, CH2 / C = C, or -HC = CH-; And it is O, S or NH; A is a 3-7 membered, saturated ring, optionally having 1 or more heterocyclic hetero, Ci_6 alkyl oyl ester, phenylalkyl tone, alkylpro-quilalcanamide, acetic acid, or di-amides; Z 1 is C o; denotes the presence or absence; R1, R2, R3 each independently of an ether or oxidized form of sulfur such uro, sulphone, sulfan, sulfinimide or sulfonyl, nitro, amino, alkyl, formyl, oxyalkyl, alkoxy, cyano, carboxy, oxylic, an acid ester carboxylic, or carboxylic acid such as -. { C = 0) -N. { RxRy) ico, acetic acid ester, acid amide includes an acetic acid acetic acid hydroxyalkylamide, wherein one independently can be H, oalkyl, dialkylaminoalkyl, arylamino-amino-aminoalkyl, or heteroaryl-arainoalk wherein both groups attached to the aminoalkyl atom, together with the N n atom attached, can be joined to form a rocyclyl; or a salt, prodrug, hydrate, ore, enantiomer or mixture Acceptically acceptable thereof.

In a preferred embodiment, the composition with the formula IV is incorporated pharmaceutical ulation together with pharmaceutical agents, excipients or vehicles. , or ? (?? p) where : ? it is a ring of 4-10 members, saturated, which may be mono-, bi-, or tri- cyally may have one or more heteroatoms; D is phenyl, a carbocycle or a hetter of which is optionally substituted; Z is H, SH and thioalkyl, hydroxy, halogen or, formyl, alkylamino-heterocycle, dialk one independently is H, alkyl, halogen, iohalogen, or heteroalkyl; or R is a alkylcarbon which optionally binds at any carbon atoms attached to the phenyl ring at or, whereby a dicalic structure is formed; Y W is O, S, CH2 or NH, or a tautomer or in themselves.

The compounds of the formulas V-VIII are the synthesis of compounds of the formula I-IV.

Also within the scope of the invention are compounds 1-86, and a pharmaceutic salt thereof.

In addition, the present invention provides methods and methods of modulation and / or inhibition of Aurora kinase that is unregulated or altered to control the efficacy of certain existing cancer chemotherapies.

Additional modalities of this uyen: a compound in accordance with any I-IV clauses for use as a medicament; the step in accordance with any of the formulas the preparation of a medicament for the subject-matter that needs inhibition of a protein c of the compound in accordance with any cell I-IV for the preparation of a drug sion or reduction of cell proliferation, which stasis of cancer, leukemias, and enf oproliferativas; A pharmaceutical composition renders an effective amount of a compound of formulas I, II, III or IV and a vehicle, excipient pharmaceutically acceptable; a method of Detailed Description of the Invention I. Introduction The present invention relates to computers, regulate and / or modulate the transduction of s of the protein kinases and by the particular Auror. The invention also relates to compositions comprising these compounds, more compounds in the treatment of diseases related to Aurora, to synthesize the compounds. In cto, the present invention provides a structure compound according to formula I: R "each independently is H, genoalkyl, alkylohalogen, or heteroalkyl, na heteroalkyl which optionally binds in emo to attached carbon atoms of the ring is attached, whereby a cyclic structure is formed; Rlt R2, R3, each independently is ether or oxidized form of sulfur such as an ona, sulfan, sulfinimide or sulfonamide; halogen, or alkyl, formyl, hydroxy, hydroxyalkyl, or, carboxy, carboxylic acid, an oxylic ester, a carboxylic acid amide such as Ry), acetic acid, acetic acid, or acetic acid ester including an acido acid amide e substitutions - (C = 0) - (R x R y), substituted aryl, heterocyclic alkoxy, heterocycle or healkyl, or heteroaryl-aminoalkyl; and where you attached to the N atom of an aminoalkyl group the N atom to which they are attached, can bind a heterocyclyl group n is 1, 2, 3 or 4, with the proviso that = 0 when X is different from oxygen; or a pharmaceutically ideal salt, prodrug, hydrate, solvate, mica, tautomer or enamer.

In a first preferred embodiment of the f F, X is NH, and W is O.

In a second preferred embodiment of the f H, X is NH, and W is O.

In a third preferred embodiment of the f CF3, X is NH, and W is O.

In a fourth preferred embodiment, R is 3, o-alkylene linked to the phenyl ring for form.

In another preferred embodiment, the rescripts in greater detail have the meaning, but in which in the subformula la, W is 0, X is NH, n = in subformula Ib, W is 0, X is NH, n is initially Cl and a 1,3-dioxo chain to the phenyl ring to form 1,3-dioxolane; in subformula Ic, W is O, X is O, n = in the subformula Id, W is S, X is CH2 in the subformula le, W is NH, X is CH2 ; (?) where : X is H, NH-C (= 0) H, NH-CH2, (-C = 0) NH, NH, S02NH, CH2, -C = C-, -HC = CH-, or a heterocycle; And and w each one independently is 0, S or A is a 3-7 membered ring, saturated, optionally having 1 or more hetero optionally substituted; Cy is selected from the group consisting of unsubstituted or substituted alkyl, bicycloal Ry), substituted or unsubstituted aryl, heterocyclic, heterocyclic or substituted heteroaryl, alkylamino, dialkylamino, alkylaminoalkylaminoalkyl, alkyldiamino, alkylamyldiaminoalkoxy, heterocyclic alkoxy, dialkylammoxyalkylalkyl carboxylic acid alkylamide, hydroxy alkylamido dihydroxy ester - alkylamide, acetic acid oxyalkylamide; wherein R x and R y c may independently be H, alkyl, aminalkylaminoalkyl, arylaminoalkyl, caalkyl, or heteroaryl-aminoalkyl; and where the N atom of an aminoalkyl group is attached to the N atom to which they are attached, a ar can be a heterocyclyl group; or a salt, prodrug, hydrate, solvate, t In a third submodality of the preferred lity, Cy is f luorome ti 1) phenyl.

In a fourth submodality of the preferred lity, Cy is 2-f luoromet il phenyl or 2-f luoromet il phenyl.

In a fifth submodality of the preferred lity, Cy is 2,4-, 2,6-, 3,4-uorofeni lo.

In a second preferred embodiment of UIA II, X is NH, W is 0, Y is O, A is cyclohexanyl, and x, R2 / R3 and R / c is dependently H.

In a third preferred mode uía II, X is O, W is O, Y is O, A is fe (??) where : X is NH, NH-C (= 0) H, NH-CH2, (-C = 0) H, NH, S02NH, CH2 / -C = C-, or -HC = CH-; Q is NH (C = Y) or (C = Y) NH; And and W each independently is O, S or Z 'is CH or N; A is a 3-7 membered ring, saturated, optionally having 1 or more carboxylic acid amide such as - (C = 0) -N (R x R y, acetic acid ester, acid amide or an amide of acetic acid having 0) -N (RxRy) substituted, substituted or unsubstituted aryl, heterocyclic or substituted heteroaryl, alkylamino, dialkylamino, alkylaminoalkylamino, alkyldiamino, alkylamyldiaminoalkoxy, heterocyclic alkoxy, dialkylammoxyalkyl- carboxylic acid alkylamide hydroxy, hydroxy alkylamide dihydroxy-alkylamide ester, acetic oxyalkylamide acid, wherein R x and R y c may be H, alkyl, amino quilaminoalkyl, arylaminoalkyl, cakalkyl, or heteroaryl-aminoalkyl; and where you are bonded to the N atom of an aminoalkyl ethoxyphenyl group.

In a second submodality of the eride, Cy is methylphenyl.

In a third submodality of the residue, Cy is 2-fluoro-4-trifluoromethylphenyl.

In a fourth submodality of the eride, Cy is A-chlorophenyl.

In a fifth submodality of the residue, Cy is A- trifluoromethoxyphenyl.

In a sixth submodality of the eride, Cy is 2,4-, 2,6- or 3,4-dichlorophenyl.

In a second preferred embodiment of X is NH, A is phenyl, Cy is naphthyl, W and Y is independently O, and R, R2 and R3 are H.

In another preferred embodiment, the terms in greater detail have the meaning ofenyl or dichlorophenyl; in subformula Illf, Q is NH (C = 0) yl; in subformula Illg, Q is NH (C = 0) ornil; in subformula Illh, Q is NH. { C = 0) luoromethoxyphenyl; in subformula IIIj, Q is (C = 0) NH, W is and A and Cy are phenyl; in subformula Illk, Q is (C = 0) NH xyphenyl; in subformula Illm, Q is (C = 0) NH lphenyl; in subformula Illn, Q is (C = 0) NH and Cy e luoromethylphenyl; in sub-formula IIIo, Q is (C = 0) NH where : X is NH, NH-C (= 0), NH-CH2 / (-C = 0) NH, NH-C. { 02NH, CH2, C = C- O -HC = CH-; And it is O, S, or NH; A is a 3-7 membered ring, saturated, optionally having 1 or more heterons optionally substituted; Cy is selected from the group consisting of Z »is C or N; denotes the presence or absence of a Ri, R2 / 3 each independently is H, or oxidized form of sulfur such as a sulfide, anus, sulfinimide, or sulfonamide; halogen, nitrile, formyl, hydroxy, hydroxyalkyl, alkoxy oxy, carboxylic acid, an ester of carboxylic acid amide acid such as - (C = 0) - (R x R y, acetic acid ester, acid acide amide amide of acetic acid having 0) -N (RxRy), substituted or unsubstituted aryl radical, heterocycle or substituted heteroaryl, alkylamino, dialkylamino, alkylaminoalkylaminoalkyl, alkyldiamino, alkylamyldiaminoalkoxy, heterocyclic alkoxy, dialkylamine carboxylic acid alkylamide a salt, prodrug, hydrate, solvate, racemic t a, or pharmaceutically enantiomer itself.

In a first preferred embodiment of the X is NH, A is phenyl, Y is O, Cy is phenyl, Ri, one independently is H, and Z is chlorine.

In a second preferred embodiment of the X is NH, A and Cy each independently is f, Ri, R2 and R3 each independently is H, tilamino-piperidina.

In a third preferred embodiment of the X is NH, A and Cy each independently is f, i, R2 and R3 each independently is H, tilamino-ethylamine.

In a submodality of the third eride, Z is dimethylamino-propylamine. eride, Z is dimethylamino-propoxy.

In a sixth preferred embodiment of the NH, A and Cy each independently is feni i / R2 and R3 each independently is H, olidinyl-ethoxy.

In a seventh preferred embodiment of the X is NH, A and Cy each independently is / R-i / R2 and ¾ each independently is H, olinyl-propoxy.

In a submodality of the seventh erida, Z is morpholinyl-ethoxy.

In another preferred embodiment, the residues in greater detail have the meaning, but in which in the sub-formula IVa, Ri e A is phenyl, Cy is phenyl, and Z is 4-dimethe ridine; olidinylpropoxy; in subformula IVg, W is O, Y is 0, X is lo, Cy is difluorophenyl, Ri is phenyl and / OXY1CO; in subformula IVh, W is O, Y is 0, X is io, Cy is difluorophenyl, and Ri is tilaminoeti1carboxylic amide; in subformula IVj, W is O, Y is O, X is lo, Cy is difluorophenyl, and Z is droxypropylcarboxylic amide; in subformula IVk, W is O, Y is 0, X is io, Cy is difluorophenyl, and R2 is methylacetic acid in subformula IVm, W is O, Y is O, X is io, Cy is difluorophenyl, and R2 is oxyethylacetic amide.

Also encompassed by the present invention are therapeutically acceptable, and which also optionally be packaged as a kit.

In a further aspect, the invention provides for treating or preventing a disease or condition of a selected member of cancers such as acute or chronic oxygen, tumor formation, angulation, myeloproliferative disease, ocular artery diseases, inflammatory diseases, stenosis, among others. . The method includes administration in need of a therapeutic amount of a compound of formula I, formula II, or formula IV, or a salt, prodrug, enamer, hydrate, solvate or racemic mixture of the same.

In a fifth aspect of the present invention an intermediary compound of the formulas V-B is a 4-10 membered ring, saturated, which may be mono-, bi-, or tri- trically may have one or more heteroatoms; D is phenyl, a carbocycle or a hetter of which is optionally substituted; Z is H, SH, hydroxy, halogen, amino-yl, alkylamino-heterocycle, dialkylamino-het-ylamino-alkylamino, dialkylamino-alkylamino-alkoxy, dialkylamino-alkoxy, hete xi, Ci-6 alkyl ester, phenyl, alkyl ketone, alkylpropanoyl, dialkylalka or acetic; R is H, halogen, cyano, nitro, luoromethyl, an unsaturated or saturated ring or more heteroatoms such as piperazine or pi) -, heteroalkyl, OR ', SR' and NR'R ", wherein it, naphthyl or cyclohexyl; is one or more, halogen or trifluoromethyl, W is oxygen or a heterocycle, preferably pyrimidine, formyl, z-butyl hydroxypropanoate, or acetic acid or dimethylpropanamide, The compounds V-VIII are useful in the synthesis of computer formulas. -IV.

Also within the scope of the invention are compounds 1-80, and a pharmaceutic salt thereof.

Additional modalities of the present invention: a compound in accordance with any of the I, II, III or IV clauses for use as a composite device in accordance with any of the I, III or IV for the preparation of a medicament of a subject in need , inhibition of mixtures thereof in all the relationships in therapy, such as treatment of a inhibition of a protein kinase, in to have a proliferative or inflammatory disease A method for synthesizing the compounds of the invention is also encompassed within the concept.

The present invention also relates to a compound of any of the formula III or IV together with the active ingredient of a meiotic for the treatment of a subject that I am experiencing for a malfunction related especially to diseases such as angi e s such as acute myelogenous leukemia. or myeloproliferative disease, formation, tumor growth, arteriosclerosis, diseases the treatment of solid tumors characterized in Aurora kinases that are strongly expressed. These solid tumors include monocytic entymia, brain, dromae, ovarian, urogenital carcinoma of the lymphoma, laryngeal and lung system, including adenocarcinoma and small cell lung carcinoma.

In addition, the present invention provides compositions and methods of modulation and / or inhibition of Aurora kinase unregulated or altered for proliferative diseases including cancers, comprising administering to a site thereof an effective amount of an inhi sa according to any of the formula or IV. In particular, the compounds of fo III or IV are useful in the treatment of expressed cert. These solid tumors include monocytic enteritis, brain, dromae, ovarian, urogenital carcinoma of the lymphoma, laryngeal and lung system, including adenocarcinoma and small cell lung carcinoma.

The compounds of the present invention? antiproliferative in vivo in a transplant model for its inhibitory action on lar. Therefore, when administered to a patient with a hyperproliferative disease, such a myeloproliferative disease, these tumor-forming compounds reduce inflammation as well as lymphoproliferative disease, inhibit re planing, inhibit neurological damage due to bruising, etc. The compounds of the present invention are prophylactic or therapeutic purposes. The p II .. Definitions As used herein, a description of the invention in each case includes ato, hydrate, prodrug, tautomer, ena reoisomer, analog or pharmaceutically derived thereof, which includes mixtures of the various ratios.

Where the groups are substituted by their conventional chemical formulas from left to right, optionally resulting from writing the left-hand structure, e.g., -CH20- optionally ea-OCH2-.

The term "alkyl", as such or as a member, unless otherwise indicated as saturated or unsaturated hydrocarbon, of unsaturated alkyl groups includes vinyl, 2-plyl, 2-isopentenyl, 2-butadienyl, 2, 4-pentyloyl, 1-propenyl, 3-propenyl, 3-butynyl, and is thereof. One to seven atoms of alkyl chain hydr as defined can be ree F, Cl and / or Br, and / or one or two CH2 can be ree groups O, S, SO, S02 and / or CH = CH.

The term "alkylene" denotes an optionally substituted (linear) or branched radical or part of another substituent signifying the divalent derivative of an alkane, such as is H 2 CH 2 -. "Alkylene" preferably denotes enel, propylene, isopropylene, butylene, isobutyl or tert-butylene, pentylene, 1-, 2-6-3-methyl, 1,2- or 2,2-dimethylpropylene, 1-ethylpropylene, 2-, 3- or 4-methylpentylene, 1,1-, 1,2-, 1,3-, 2, eribly denotes cyclopropylene, cyclopentyl, cyclohexylene or cycloheptylene.

The term "aryl" means, unless otherwise, a single ring or unsaturated, aromatic rings, preferably of ions, the latter of which are covalently fused. The term "aryl" denotes phenyl, phenyl, o-, m- or p-tolyl, o-, m- or p-et m- or p-propylphenyl, o-, m- or p-isopropylphenyl, r-butylphenyl, o-, m- or p-hydroxyphenyl, o-, ofenyl, o-, m- or p-aminophenyl, o-, m-lamino) phenyl, o-, m- or p- (N-methylaminocarboni m- or p- -acetamidophenyl, o-, m- or p-methoxyphenyl, oxyphenyl, o-, m- or p-ethoxycarbonylphenyl, o-, -dimethylamino) phenyl, o-, m- or thylaminocarbonyl) phenyl, o-, m- or p - (N-ethylamino rbonyl) phenyl, o-, m- or p- (3-oxomorpholin-4-yl) fe p- (piperidinylcarbonyl) phenyl, o-, m- or p- [2- () ethoxy] phenyl , o-, m- opylamino) propoxy] phenyl, o-, m- or p- [3- (3-die il) ureido] phenyl, o-, m- or ilaminopropoxycarbonylamino) phenyl, erically 2,3-, 2,4-, 2,5-, 2,6-, 3,4-uorophenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4 -orophenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4-omophenyl, 2,4- or 2,5-dinitrophenyl, 2,5-toxophenyl, 3-nitro- 4-chlorophenyl, 3-amino-4-cyc-3-chloro-, 2-amino-4-chloro-, 2-amino-5-chloro- or orophenyl, 2-nitro-4-N, N-dimethylamino- or 3-Nityl-aminophenyl, 2,3-diaminophenyl, 2,3,4-, 6-, 2,4,6- or 3,4,5-tri-chlorophenyl, ethoxyphenyl, 2-hydroxy-3, 5 -dichlorophenyl, p-io (C = 0) NH2 wherein R is H or alkyl.

The term "heteroaryl" refers to one or containing one to four heteroatoms sele, 0, S, Si, P and B, wherein the nitre atoms are optionally oxidized, and the oxygen atoms are optionally quaternized. U roaril can be attached to the remainder of the carbon or heteroatom molecule.

Non-limiting examples of roaryl groups include phenyl, 1-naphthyl, 2-naphthyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolidolyl, 2-imidazolyl, 4-imidazolyl, pyrazolyl, 4-oxazolyl, 2-phenyl- 4-oxazolyl, 5-oxazo-ayazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-thiazo-olyl, 5-thiazolyl, 2-furyl, 3-furyl, 2-tieyl, 2-pyridyl, 3-pyridyl, 4-pyridyl , 2-pyrim oxy, arylthioxy or arylalkyl, optionally including aryl or heteroaryl as defined, the term "arylalkyl" optionally the radicals in which an aryl group is or alkyl (eg, benzyl, phenethyl, pyridyl) which includes those alkyl groups on the carbon atom (e.g., a methylene group) placed, for example, by an oxygen atom ximethyl, 2-pyridyloxymethyl, 3- (1-naphthyloxy) pr ). Each of the terms "eroalkyl, 11" aryl "and" heteroaryl "optionally substituted unsubstituted, mono-, di- or oluido forms of the indicated radical.

The terms "alkoxy," "alkylamino," and "a thioalkoxy" are used in their conventional sense to those alkyl groups attached to the substituted or unsubstituted radical, heteroaryl their substituted, heterocycloalkyl substituted or not their lt where Ri is -OH , O-alkyl, -CN, -halogen,) O (alkyl), -C (0) NH2, -C (0) NH (alkyl), -C (0) N (a OH, -CH20 (alkyl), -CH2NH2, -CH2NH (N (alkyl) 2, -S020H, -S020 (alkyl), H (alkyl), and -S02N (alkyl) 2. From the above substituents, one skilled in the art the term "alkyl" includes groups including arbono attached to groups other than the groups S as haloalkyl (v. gr., -CF3 and -CH2CF3) and acyl) CH3 / -C (0) CF3, -C (0) CH2OCH3, and the like).

Similar to the substituents described as alkyl alkyl, the substituents for the roaryl groups are generically referred to as "sust rupo aryl". The substituents are selected onyl, C (0) R. Illustrative species for R inc geno, substituted or unsubstituted alkyl substituted or unsubstituted, substituted heteroaryl, and substituted or unsubstituted heterocycloalkyl As used herein, the term "if fused" means at least two years and each ring has at least 2 ring atoms. Fused ring systems can be aromatic as well as non-aromatic. Axis fused ring themes "are naphthalenes, olinas, cromenos, norbornans and norbornenos replaced, and the like.

The term "treatment", as used enté, refers to prevention of an icicle or to treatment of a pre-existing condition.

The phrase "therapeutically effective amount" means salts of the active compounds which are relatively non-toxic bases or bases are particular ingredients found in the teachings herein. When the compounds of the invention contain related functionalities, the basic addition salts can be contacted in the neutral form of those compounds sufficient in the desired base, either in a suitable inert solvent. Examples of pharmaceutically acceptable addition salts: sodium, calcium, ammonium, organic amino or magnesium salt, lar. When the compounds of the present invention have relatively basic functionalities, the addition compounds can be obtained by neutralizing said compounds with a desired acid amount, either in net form or in an ico, benzenesulfone, p-tolylsulfonic acid. , aric, methanesulfonic and the like. S are also amino acids such as arginate and the like, organic acids such as glucuronic acids or galactones (see, for example Berge et al., J pharma., 66: 1-19). Certain specific compounds of the invention contain basic functionalities that allow the compounds to be converted to suitable addition acids.

The neutral forms of the compounds are regenerated by contacting the base or acid and isolating the original compound of the element. The original form of the compound differs from salt forms in certain properties as solubility in polar solvents, but the salts are equivalent to the pharmaceutical origins form of the present invention carboxylic acid. In another ilu prodrug modality, suitable for treatment / prevention, the diseases and conditions that require a drug to cross the blood-brain barrier preferred modality, the prodrug enters the ce e is converted to the active form of the molecule. In addition, prodrugs can be converted to the present invention by chemical methods in an ex vivo environment.

For example, prodrugs can be extended to the compounds of the present invention by placing in a transdermal patch reservoir or suitable chemical reagent.

Certain compounds of the present invention in unsolvated forms as well as "is intended to have the meaning including that materials satisfying more than one established term are included, eg, a salt mate as a solvate. it is covered.

As used herein, the eroatom "includes oxygen (0), nitrogen (N), az cium (Si), boron (B), and phosphorus (P).

The term "heteroalkyl" as such an ination with another term means, unless otherwise stated, a stable or cyclic branched chain hydrocarbon radical, or combinations thereof consisting of an established number of atoms of at least one heteroatom selected from the group. O, N, Si and S, and wherein the UFre atoms may be optionally oxidized and the nitrogen may optionally be quaternized "eroalkyleneo", as such, or as a component thereof means a radical divalent radical, as illustrated, but is not limited to -CH2-S-CH2-CH2- and -CH2-S-CH2-CH2-NH-CH2-. roalkylene, the heteroatoms may also or both of the terminal ends of l, alkyleneoxy, alkylenedioxy, alkylenediamino, and the like.) In addition, for hetero and heteroalkylene groups, there is no implication of the linker group by the written direction. The formula of the linker group, for example, -C02R'- represents both -C (0) OR 'and -OC (0) The terms "cycloalkyl" and "heterocycle such or in combination with other terms, referents otherwise indicated, cyclic versions" and "heteroalkyl", respectively. In addition, 5,6-tetrahydropyridyl), 1-piperidinyl, 2-pipe peridinyl, 4-morpholinyl, 3-mor-ahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrah, tetrahydrothien-3-yl, l-piperazinyl, 2-pipe milares.

The terms "halo" or "halogen" as such and of another substituent, mean, unless at least one fluorine, chlorine, bromine or iodine atom such as "halogenoalkyl" is understood to be monohaloalgalyl and polyhaloalkyl, the term "Halogenoalkyl (Ci-C4)" includes, mimics trifluoromethyl, difluoromethyl, fluo-2-trifluoroethyl, 4-chlorobutyl, 3-bromopropres.

The terms "TEA", "DMF", "LDA", "DCM" and here as reagents in the synthesis of compounds or chiral reagents, or can be solved by conventional techniques. When the currencies in the present contain double bonds or centers of geometric asymmetry, and unless otherwise stated, it is intended that the geometric isomers be both E and Z.

Also, the tauromeric forms are included. The term "host" or "patient" which ne or ", as used herein, may be mammalian, for example, a species of human, rodents, rabbits, horses, dogs. , cats, etc. Animal models are from veterinary treatment and for research, which provide a model for human trafficking.

The susceptibility of one. cell partia sia. The viable cells left behind were counted.

The dose of the drug depends on the chemical used, the specific disease, the condition, etc. A therapeutic dose is considerable enough to reduce unwanted populations in the target tissue while the patient's condition is maintained. The treatment is continued until a population of cells has occurred, for example, by 50% of the reduction in the load of cells being continued until essentially and they cite more unwanted cells in the body.

Pharmaceutical Compositions Although the compounds of the present invention are ingredients of the formulation and do not disclose them. The term "pharmaceutically acceptable" includes vehicles, dipents and other elements suitable for incorporation of pharmaceutical formulations.

A formulation of a compound or any suitable for administration includes subcutaneous, intradermal, intravenous, peritoneal and intraarticular), orthorheic, intranasal, inhalation and oral (such as ica, buccal, sublingual and intraocular). The condition may depend on the condition and disorder. The formulations may be preferably in a unit dosage form or prepared by any of the well-known pharmacy methods. All methods include the technique and the general methods to prepare enter into any pharmacy textbook example, Remington: The Science and Prac macy. , A.R. Gennaro, ed. (1995), which is described here by reference in its entirety.

Pharmaceutical compositions which are put in formulas I, II, III or IV are conveniently in a pharm dosage form by any of the well-known pharmacy methods. The missed dose formulations are those that contain a dose of an appropriate fraction thereof, of the pharmaceutically acceptable salt ingredient thereof. The prophylactic or therapeutic dose typically has the severity and severity of the condition and the route of administration. The dose and Ximately 50 mg to about 500 mg can be from approximately 100 mg to approximately mg per day. It is also recommended that children, aged 65 years and those with renal or rada function, initially receive low doses and that the lada based on the responses and / or levels in viduales. It may be necessary to use out-of-dose doses in some cases, as is evident in the art. In addition, it should be noted that the physician or the treating physician knows how to interrupt, adjust or terminate the therapy and the individual patient.

The formulations herein for oral administration may be presented discretely such as capsules, cachets or one of which contains a suitable predetermined amount of the active ingredient in such form as a powder or granules, optionally, a binder, lubricant, inert diluent, surface level or dispersing agent. The eads can be made by molding in a machine mix of the powdered compound moistened with an inert gone. The tablets can be optional or marked and can be formulated for sustained, delayed or controlled ration of in VO in them. Sustained oral and parenteral release delivery systems are well known to those skilled in the art, and methods for generating sustained oral drug release are, for example, found in Remin NCE AND PRACTICE OF PHARMACY, 21st Ed., (1995) - 75 It should be understood that in addition to the blood with the recipient blood alloys for parenteral administration also sterile aqueous and non-aqueous secretions, which are suspending agents and thickening agents, the formulations for oral administration to include flavoring agents. The formulations are presented in unit dose of iple containers, for example sealed vials and flasks, stored in a dried condition by conglomeration) which requires only the addition of a sterile product, for example, saline solution, regulated at its pH with phosphate (PBS) or diately before use. The solutions and their extemporaneous nyección can be prepared to p os, granules and sterile tablets of the ante rito type. The formulations for administration r variety of forms, according to the administration route, for example, oral or parenteral (that avenosa). In the preparation of the oral composition, any of the pharmaceutical media can use, such as water, glycols, holes, flavoring agents, preservatives and preservatives in the case of liquid preparation or suspension, elixirs and solutions. Vegetables, sugars, microcrystalline cellulose, granulating agents, lubricants, disintegrating agglomerates can be used in solid oral arations such as powders, castes, where the solid oral preparation is in the liquid preparations. Preferred preparations are tablets or capsules, administration de? Ciency. If desired, the tablet of disease / condition with the active agent which can be solid in the kit comprises a compound of the present invention in a syringe, box, bag and caly, the kit comprises of instructions nistración compound. The particularly advantageous form when different concentrations and / or dosage forms (e.g., oral and stop at, or when the titration of the combinations of the desired combination by the doctor.

An example of a kit of this type is the bubble type. Bubble packs are used in the packaging industry and are widely packaged in unit dosage forms (farm letas, capsules and the like). Generally cooking in which depressions were formed. In particular, it is usually stamped on a cad urbuj as.

In another specific embodiment of the invention is a dispenser designed to supply them one at a time in the order of use. intended.

III Methods of Treatment or Prevention In a further aspect, the invention provides for the treatment or prevention of an inflammation which is a selected member related to kinase ionization, and especially diseases such as angiogenesis, cancers, tumor growth and spread, ocular artery diseases such as acid degeneration. by age, colocaceutically acceptable neovascularization thereof.

Subjects for the treatment of the present invention include humans (patients) who need therapy for the establishment.

The compounds of the invention have unique pharmacological characteristics with respect to cell division and influence of the enzymes Aurora kinases in the cells. By 1 S compounds are effective to treat conditions specifically tumors and tr cionados with cancers, which are modulated by a urora kinase. In one modality, the compounds are associated with negative effects in comparison with the traffic techniques. r IV General Summary The compounds of the invention are prepared by methods known to those skilled in the synthesis of analogous compounds. These are the general schemes indicated below, the preparations that follow. Most starting materials are commercially available from suppliers such as Aldrich Chemicals Co. Company, as examples. The compounds that are available in a conventional manner can be synthesized in the art by following procedures such as "Organic Reactions", Vol. Wiley & Sons (1991); "Rodd's Chemistry o ounds", Volumes 1-5 and Suppl., Elservier ishers (1989); "Fieser and Fieser's Reagents for hesis," Volumes 1-15, John Wiley & Sons (Reaction Scheme the where R is as defined here for l The product of scheme 1 or the scheme the following synthesis of scheme 2 based on mé is contained in WO 05/056552 d maceuticals Incorporated, whose content is in by reference.

Reaction Scheme 2 where : R is H, halogen, cyano, nitro, a luoromethole, heteroalkyl, OR ', SR' and NR e R 'and R "each independently ilo, halogenoalkyl, alkylohalo roalkyl, or R is a heteroalkyl chain it is attached at either end to the attached phenyl ring to the attached ones, whereby a bicyclic structure is formed; n is 1, 2, 3 or 4, with the condition of being = 0 when X is different from oxygen.

Reaction Scheme 3 An alternative synthesis route for sites of the present invention is given Reaction Scheme 4 Piperidine CH2 (C02 e) 2 6 by a ligand-linked chain containing an aryl or heterocyclic moiety added preferred aryl ion is a substituted phenyl group m, and illustrative heterocyclic moieties such as piperazinyl groups, pipe hatexolinyl, furanyl, benzofuranyl, or azolyl, thiazolyl, isothiazolyl, imidazo zolyl.

The following examples are provided for selected properties of the invention and be devised as limiting their scope.

Examples Example 1 N- (4-Aminophenyl) -2-f-Exobenzamide ipitated (1.5 g) was filtered and dried. I) and trifluoroacetic acid (15 ml) were suspended and stirred minutes. The solvents were removed, and the solution was taken up in EtOAc / water and the pH was adjusted to 10 with potassium salt. The EtOAc layer was separated and extracted with more EtOAc. The organic layer with water once, dried over MgSO4. The product obtained after concentration, the reaction was used without further purification. LCM)].

Example 2 N- (5-Amino-pyrimidin-2-yl) -benzamide The crude product (820 mg) was used for the preparation - without further purification. LCMS [215.2 (M + l Example 3 N- (4-Aminophenyl) -3-fluoro-benzamide The title compound (910 mg) is synthesized with the procedure described for Example 1 by the use of N-Boc-1,4-phenyl g), 1. eq. of triethylamine and 3-benz LCMS chloride [231.2 (M + 1)].

The title compound (880 mg) was synthesized with the procedure described for Example 1 with N-Boc-1, 4-phenylenediamine (1.0 g), rietylamine and 4-benzoyl chloride (1.1 eq). LC] · Example 5 N- (4-Aminophenyl) -2-trifluoromethyl-benzamide The title compound (920 mg) is Example 6 N- (4-Aminophenyl) -4-trifluoromethyl-benzamide The title compound (900 mg) was synthesized with the procedure described for Example 1 with N-Boc-1,4-phenylenediamine (1.0 g), rietylamine and 4-trifluoromethyl-benzo LCMS chloride [281.25 (M + l)].

Example 7 N- (4-Aminophenyl) -2-fluoro-3 trifluoromethyl-benzai oyl (1.1 eq). LCMS [299.2 (M + l)].

Example 8 N- (4-Aminophenyl) -4-fluoro-2-trifluoromethyl-benz The title compound (900 mg) was synthesized with the procedure described for Example 1 with N-Boc-1,4-phenylenediamine (1.0 g), triethylamine and 4-fluoro-2-trifluoryl chloride (1.1 eq. ). LCMS [299.2 (M + l)].

Example 9 Riethylamine and 2,6-difluoro-benzoyl chloride [249.2 (M + l)].

Example 10 N- (4-Aminophenyl) -3, -difluoro-benzamide The title compound (850 mg) was synthesized with the procedure described for Example 1 with N-Boc-1,4-phenylenediamine (1.0 g), ritylamine and 3,4-difluorobenzoyl chloride [249. (M + I)].

The title compound (720 mg) is in accordance with the procedure described in Example 1 with the starting materials of N-Boc-1,4-phenylenediamine (1.0 g), triethylamine and 3,5-dif luoro-b chloride. eq). LCMS [249.2 (M + l)].

Example 12 N- (4-Aminophenyl) -2, -difluoro-benzamide The title compound (810 mg) is if Example 13 (4-Aminophenyl) - cyclohexanecarboxyamide The title compound (550 mg) is synthesized with the procedure described for Example 1 with N-Boc-1,4-phenylenediamine (tilamine (1.1 eq) and cyclohexyl chloride (1.1.3 (M + l)] .

Example 14 N- (4-Aminophenyl) -3,5-bis-trifluoromethyl-benzam oyl (1.1 eq). LCMS [349.2 (M + l)] (4-Aminophenyl) na-2-carboxylic acid amide The title compound (700 mg) is synthesized with the procedure described for Example 1 with N-Boc-1, phenylenediamine (tilamine (1.1 eq) and 2-naphthoyl chloride (1.1.1 (M + l) ] The title compound (750 mg) is based on the procedure described in Example 1 with N-B lendiamine (1.0 g), triethylamine (1.1 urea of 2-methoxy-benzoyl (1.1 eq), LCMS)] - Example 17 N- (4-Aminophenyl) -4-methyl-benzamide Example 18 N- (4-Aminophenyl) -2-fluoro-4-trifluoromethyl-benz The title compound (890 mg) was synthesized with the procedure described for Example 1 with N-Boc-1,4-phenylenediamine (tilamine (1.1 eq) and 2-fluoro-4-trifluoryl chloride (1.1 eq). LCMS [299.2 (M + l)].

Example 19 Example 1 with N-Boc-1, 4-phenylenediamine (tilamine (1.1 eq) and 3-fluoro-5-trifluoryl chloride (1.1 eq) LCMS [299.2 (M + l)].

Example 20 N- (4-Aminophenyl) -4-chloro-benzamide The title compound (780 mg) is based on the procedure described in Example 1 with N- Example 21 (4-Amino enyl) -4-ri luorornetoxy-benzamide The title compound (750 mg) was synthesized with the procedure described for Example 1 with N-Boc-1,4-phenylenediamine (tilamine (1.1 eq) and 4-trifluoromethoxy chloride). LCMS [297.2 (M + l)].

Example 22 N- (4-Aminophenyl) -2-methyl-benzamide tilamine (1.1 eq) and 2-methyl-benzoyl chloride LCMS [227.2 (M + l)].

Example 23 N- (4-Aminophenyl) -3-methyl-benzamide The title compound (710 mg) is synthesized with the procedure described for Example 1 with N-Boc-1, 4-phenylenediamine (tilamine (1.1 eq) and 3-methyl-benzoyl chloride ( [227.2 (M + l)].

The title compound. { 750 mg) was synthesized with the procedure described for Example 1 with N-Boc-1, 4-phenylenediamine (tilamine (1.1 eq) and 1-naphthoyl chloride (1.1 e .1 (M + l)].

Example 25 N- (4-Aminophenyl) -2,6-dichloro-benzamide The title compound (940 mg) is in accordance with the procedure described Example 26 N- (4-Aminophenyl) -3,4-dichloro-benzamide The title compound (890 mg) is synthesized with the procedure described for Example 1 with N-Boc-1,4-phenylenediamine (tilamine (1.1 eq) and 3,4-dichlorobenzoyl chloride LCMS [281.1 (M + l)].

Example 27 N- (4-Aminophenyl) -2,4-dichloro-benzamide tilamine (1.1 eq) and 2,4-dichlorobenzoyl chloride LCMS [282.1 (+ l)].

Example 28 N- (4-chloropyridin-2-yl) -2, 2-dimethylpropanamid To a solution of 4-c-loropyridin-0 g; 64.56 mmoles; 1.00 eq.) In DCM / 100 ml) was added N, -diethylethanamine (0 mmole, 1.25 eq.), Followed by tylpropanoyl chloride (8.56 g, 71.02 mmole, 1.1 Example 29 - (4-chloro-3-formylpyridin-2-yl) -2, 2-dimethylpropa To a solution of N- (4-chloropyridy dimethepropanamide (3.30 g, 15.52 mmol in THF (40 mL) at -78 ° C) was added drop-lithium (15.52 mL, 2.50 M, 38.79 mmol, The mixture was stirred for 30 minutes or a solution of dimethylformamide (4.5 mmol, 3.00 eq.) in THF (10 mL). After -78 ° C, the mixture was heated to RT.

-Chloro-2- [(2,2-dimethylpropanoyl) amino] pyridine-3-hydroxypropanoate tert-butyl To a solution of - isopropylpropanmy; 29.52 minols; 2.20 eq.) In THF (3-butyllithium (11.81 mL, 2.50 Ms, 2.20 eq.) Was added The mixture was stirred for a while and cooled to -78 ° C. Tea acetate: 29.52 mmole; 2.20 eq.) in THF (5 or dropwise to the previous solution and 15 minutes, a solution of N- (4- Example 31 5-Chloro-l, 8-naphthyridi-2 (1H) -one A solution of 3-. { 4-chloro-tylpropanoyl) amino] pyridin-3-yl} -3-hydroxypro tert-butyl (3.50 g 5.60 mmoles) in aqueous cloogen (40.00 ml, 3.00 M, 75.00 mmoles) flow for 1.5 hr (continuous monitoring is necessary because warming resulted in a by-product). The cooling a precipitate, which was filtered, washed with water, and dried. The filtering was done ona Example 32 N- (4- (7-OXO-7,8-dihydro-l, 8-naphthyridin-4-ylamino) phenyl) benzamide clohexylphosphino-2'-4'-6'-tri i sopro i Ii feni 12 mg) and sodium tert-butoxide (212.86 anus (3 ml) was stirred at 100 ° C for 24 hr. After cooling to room temperature The solid was filtered, washed with water and methanol, and 20 mg of the desired product was obtained (M + 1).

Example 33 - (7-OXO-7, 8-dihydro-l, 8-naphthyridin-4-yl-amino) pi 2-yl) benzamide Example 34 2-Fluoro-N- (4- (7-oxo-7,8-dihydro-l, 8-naphthyridin-amino) phenyl) benzamide 2-Fluoro-N- (4- (7-oxo-7,8-dihydro-l, 8-naphthyrin) phenyl) benzamide was synthesized in accordance with the described procedure for the preparation of the axis [375.3 (M + l)].

Example 35 3-Flouro-N- (4- (7-oxo-7,8-dihydro-l, 8-naphthyrin) phenyl) benzamide was synthesized in accordance with the described procedure for the preparation of the axis [375.3 (M + l)].

Example 36 4-Fluoro-N- (4- (7-oxo-7,8-dihydro-l, 8-naphthyridin-4 amino) phenyl) benzamide Example 37 fluoromethyl-N- (4- (7-oxo-7,8-dihydro-l, amino) phenyl) benzamide 2-Triflouromethyl-N- (4- (7-OXO-7,8-dihydro-l, iridin-4-yl-amino) phenyl) benzamide is synthesized by the procedure described for example 32. LCMS [425.3 ( M + l)].

Example 38 4-Triflouromethyl-N- (4- (7-OXO-7,8-dihydro-l, iridin-4-yl-amino) phenyl) enamide was synthesized with the procedure described for example 32. LCMS [425.3 ( M + l)].

Example 39 -Fluoro-3-trifluoromethyl-N- (4- (7-oxo-7,8-dihydro) naphthyridin-4-yl-amino) phenyl) benzamide Example 40 -Flouro-2-trifluoromethyl-N- (4- (7-oxo-7,8-dihydro) naphthyridin-4-yl-amino) phenyl) benzamide 4-Fluoro-2-trifluoromethyl-N- (4- (7-γ-7,8-d-naphthyridin-4-yl-amino) phenyl) benzamide is synthesized with the procedure described for Example 32. LCMS [443.3 (M + l)].

Example 41 2, 6-Difluoro-N- (4- (7-oxo-7,8-dihydro-1,8-ylidin-4-yl-amino) phenyl) benzamide is synthesized by the procedure described for Example 32. LCMS [393.3 (M + l)].

Example 42 4-Diflouro-N- (4- (7-oxo-7,8-dihydro-l, 8-naphthyridine amino) phenyl) benzamide Example 43 5-Diflouro-N- (4- (7-oxo-7,8-dihydro-l, 8-naphthyridine amino) phenyl) benzamide 3, 5-Difluoro-N- (4- (7-oxo-7,8-dihydro-1, 8-riridin-4-amino-amino) phenyl) benzamide is synthesized by the procedure described for Example 32. LCMS [393.3 (M + l)].

Example 44 2,4-Difluoro-N- (4- (7-oxo-7,8-dihydro-l, 8-iridin-4-yl-amino) phenyl) -enoxamide is synthesized by the procedure described for Example 32. LCMS [393.3 (M + l)].

Example 45 N- (4- (7-OXO-7,8-dihydro-l, 8-naphthyridin-4-ylamino) phenyl) cyclohexanecarboxamide Example 46 N- (4- (7-OXO-7,8-dihydro-l, 8-naphthyridin-4-yloxy) phenyl) benzamide l-Chlorobenzo [c] -1,8-naphthyridin-6 (5H) -o .00 mg; 0.55 mmoles; 1.00 eq.) Was suspended (20 ml), and ether HC1 1N mi was added). The reaction mixture was stirred overnight. The resulting HC1 salt is Example 47 N- (2- (7-OXO-7, 8-dihydro-l, 8-naphthyridin-4-ylamino) phenyl) benzamide N- (2- (7-OXO-7,8-dihydro-l, 8-naphthyridin-yl) phenyl) benzamide was synthesized in accordance with the procedure described for the preparation of the axis [357.3 (M + l)].

Example 48 4- (7 - ??? - 7, 8-dihydro-l, 8-naphthyridin-4-yl-am ljbenzamide was synthesized in accordance with the described edification for the preparation of the axis [357.3 (M + l)].

Example 49 3, 5-Bis (trifluoromethyl) -N- (4- (7-oxo-7,8-dihydro-tiridin-4-yl-amino) phenyl) benzamide Example 50 Naphthalen-2-yl-4- (7-oxo-7,8-dihydro-l, 8-naphthyridine amino) benzamide The title compound was synthesized by the procedure described for the preparation of LCMS [407.4 (M + l)].

Example 51 The title compound was synthesized by the procedure described for the preparation of LCMS [387.4 (M + l)].

Example 52 4-Methyl-N- (4- (7-oxo-7,8-dihydro-l, 8-naphthyridin-4 amino) phenyl) benzamide Example 53 -Fluoro-4-trifluoromethyl-N- (4- (7-oxo-7,8-dihydro) naphthyridin-4-yl-amino) phenyl) benzamide The title compound was synthesized by the procedure described for the preparation of LCMS [443.4 (M + l)].

Example 54 Fluoro-5-trifluoromethyl-N- (4- (7-oxo-7,8-dihydro) The title compound was synthesized from the procedure described for the preparation of LCMS [443.4 (M + l)].

Example 55 4-Chloro-N- (4- (7-oxo-7,8-dihydro-l, 8-naphthyridin-4 amino) phenyl) benzamide Example 56 rifluoromethoxy-N- (4- (7-oxo-7,8-dihydro-l, 8-naphthi il-amino) phenyl) benzamide The title compound was synthesized by the procedure described for the preparation of LCMS [441.3 (M + l)].

Example 57 The title compound was synthesized by the procedure described for the LCMS preparation [371.4 (M + l)].

Example 58 3-Methyl-N- (4- (7-oxo-7,8-dihydro-l, 8-naphthyridin-4 amino) phenyl) benzamide Example 59 Naphthalen-l-il-4- (7-oxo-7,8-dihydro-l, 8-naphthyridine amino) benzamide The title compound was synthesized by the procedure described for the preparation of LCMS [407.4 (M + l)].

Example 60 , 6-Dichloro-N- (4- (7-oxo-7,8-dihydro-l, 8-naphthyridine) The title compound was synthesized by the procedure described for the preparation of the LCMS [426.3 (M + l)].

Example 61 , 4-Dichloro-N- (4- (7-oxo-7,8-dihydro-l, 8-naphthyridine amino) phenyl) benzamide Example 62 4-Dichloro-N- (4- (7-oxo-7,8-dihydro-l, 8-naphthyridine amino) phenyl) benzamide The title compound was synthesized by the procedure described for the preparation of LCMS [426.3 (M + 1)].

Example 63 - (4- (7-Chloro-l, 8-naphthyridin-4-yl-amino) phenyl) benz-phosphorus (30 ml) was stirred overnight at 100 ° C. Upon removal of the solvent, the crude product was reacted without further purification. LCM)] · Example 64 (4- (7 (4-Dimethylamino-piperidin-l-il-l, 8-naf iridi amino) phenyl) benzamide Example 65 - (4- (7- (-p-methylamino-ethylamino) -1,8-naphthyridin-amino) phenyl) benzamide The title compound was synthesized by the procedure described for the preparation of LCMS [427.5 (M + l)].

Example 66 The title compound was synthesized by the procedure described for the preparation of LCMS [441.5 (M + 1.)].

Example 67 - (7- (4-Dimethylamino-pyrrolidin-1-yl) -1,8-naphthyrid amino) phenyl) benz mida Example 68 N- (4- (7- (4-Dimethylamino-ethoxy) -1,8-naphthyridin-4-amino) phenyl) benzamide The title compound was synthesized by the procedure described for the preparation of LCMS [428.5 (M + l)].

Example 69 N- (4- (7- (4-Dimethylamino-propoxy) -1,8-naphthyridin-4 the procedure described for the preparation of LCMS [442.5 (M + l)].

Example 70 - (4- (7- (2-pyrrolidin-1-yl-ethoxy) -1,8-naphthyridin-amino) phenyl) benzamide Example 71 - (4- (7- (3-morpholin-4-yl-propoxy) -1,8-naphthyridin-amino) phenyl) benzamide The title compound was synthesized by the procedure described for the preparation of LCMS [484.5 (M + 1)].

Example 72 N- (4- (7- (2-morpholin-4-yl-ethoxy) -1,8-naphthyridin-4 the procedure described for the preparation of the LCMS [470.5 (M + l)].

Example 73 (3-Benzoyl-4-chloropyridin-2-yl) -2, 2-dimethylpropa To a solution of N- (4-chloropyridi dimethylpropanamide (4.00 g, 18.81 mmol in THF (40 mL) at -78 ° C was added butyl 80 mL, 2.50 M, 39.50 mmol, 2.10 eq.) The mixture was stirred for 3 hr at 0 ° C was cooled to -78 ° C again. (2-Amino-4-chloro-pyridin-3-yl) -phenyl-me anon A suspension of N- (3-benzoyl-4-chlorop 2,2 -dimethylpropanamide (400.00 mg, 1.26 mmol) Cl aq. 3N was heated to reflux overnight, cooled to rt, the mixture neutralized with NaO extracted with DCM (4x20 mL) The residue was purified by flash chromatography of silica gel for? T? E (2-amino-4-chloro-pyridin-3-yl) -phenyl-methanone.

Example 75 5-chloro-2-oxo-4-phenyl dihydro-1,8-na-tiridi-3-carboxylic acid tert-butyl ester he let The product was filtered and washed with water to provide 300 mg of the o-4-phenyl-1,2-dihydro-l, 8-naphthyridi-3-carboxylic acid tert-butyl ester .7 (M + 1)].

Example 76 gone 5- [(3, 4-difluoro-benzoylamino) -phenylamino] -2- phenyl 1,2-dihydro-l, 8-naphthyridine-3-carboxylic Example 77 (2-Dimethylamino-ethyl) -amide of 5- [(3,4-difl enzoylamino) -phenylamino] -2-oxo-4-phenyl-1,2-dihydrate naphthyridine-3-carboxylic To a solution of 5- (. {Uorobenzoi 1) amino] pheni 1 acid} amino) -2-oxo-4-phen-1, 8-naphthyridine-3-carboxylic acid (50.00 m is; 1.00 eq.) in DIVISO (2 ml) was added bis (1H-imidazole) (31.64 mg; 0.20 mmol Example 78 (2-Hydroxy-ethyl) -amide of 5- [(3,4-difluo-enoylamino) -phenylamino] -2-oxo-4-phenyl-1,2-dihydrate naphthyridine-3-carboxylic The title compound was synthesized by the procedure described for the preparation of LCMS [556.4 (M + l)].

Example 79 S) 2, 3-dihydroxypropyl) -amide of 5- [(3, -di) the procedure described for the preparation of LCMS [586.5 (M + 1)].

Example 80 or (5-chloro-2-oxo-l, 2-dihydro-l, 8-naphthyridin-3-yl) The title compound was synthesized by the procedure described for the preparation of LCMS [239.5 (M + l)].

Example 81 gone 5- [(3, 4-difluoro-benzoylamino) -phenylamino] -2- phenyl-1,2-dihydro-l, 8-naphthyridine-3-acetic LCMS [402.3 (M + l)] Example 82 (2-Hydroxy-ethyl) -amide of 5- [(3,4-difluoryl-nylamino) -phenylamino] -2-oxo-4-phenyl-1,2-dihydrate naphthyridine-3-acetic The title compound was synthesized by the procedure described for the preparation of LCMS [494.4 (M + l)]. aldehyde (4.0 g, 25.39 mmoles) and 4 / -aminobe 7 g, 30.46 mmoles, 1.2 eq.) and bicarbonate of so 0.77 mmoles, 2.0 eq) in MeOH / water (100 ml / 50 ml) ° C overnight. After cooling to solid, the solid (8.2 g) was filtered, washed co nol and then dried under vacuum. LCMS [334.3 (M + Example 84 4- (4-Benzoylamino-phenylamino 7,8-dihydro-pyrido [2,3-d] pyrimidine-6-carboxylic acid methyl ester Example 85 4- (4-benzoylamino-phenylamino) -7-oxo-7,8-dih pyrido [2 f 3-d] pyrimidine-6-carboxylic acid To a suspension of methyl ester d-benzoylamino-phenylamino) -7-oxo -7,8-dihydro [2/3-d] pyrimidine-6-carboxylic acid (00 mg is) in THF / MeOH (2 ml / 2 mi) was added N 0.48 ral, 2 eq., 0.48 mmoles) and stirred Example 86 - 4- (4-Benzoyl-enylamino) -7-oxo-7,8-dihydro-pyrido [2,3-d] pyrimidine (Dimethylamino-ethyl) -amide carboxylic The mixture of zoilamino) phenyl] amino acid} -7 -oxo- 7,8-dropirido [2,3-d] irimidine-6-carboxylic acid 0. 12 minols; 1.00 eq. ), EDCI (26.17) Example 87 Difluoro-N- (4- (6-nitro-7-oxo-7,8-dihydro-l, 8-naf 4-yl-amino) phenyl) benzamide 5 - . 5-Chloro -3-nitro-1,8-naphthyridin-2 (1H) -o .00 mg; 2.66 mmoles; 1.00 eq.) Was added (10 mL), 1N HCl ether (2 nd reaction mixture was added to t.a. during 2 Example 88).

Fluoro-2-trifluoromethyl-N- (4- (6-nitro-7-oxo-7, 8-d 1 r 8-naphthyridin-4-yl-amino) phenyl) benzamide 5-Chloro-3-nitro-l, 8-naphthyridin-2 (1H) -o .00 mg; 0.89 immoles; 1.00 eq.) Was added (10 mL), 1N HC1 ether (2%) was added, and the reaction mixture was stirred at RT for 2 hours and filtered and dried.

-Difluoro-N- (4- (6-amino-7-oxo-7,8-dihydro-l, 8-naf 4-yl-amino) phenyl) benzamide To a solution of 3, 4-di f luoro -N-? - 7 - ??? - 7; 8-dihydro-l, 8-naphthyridin-4-mino] fenyl} Benzamide (1.00 g) in DMF (ma to dissolve S) / MeOH (30 ml) is added Example 90 Fluoro-2-t.rifluoromethyl-N- (4- (6-amino-7-oxo-7, 8-d 1 r 8-naphidin-4-yl-amino) phenyl) benzamide To a solution of 4-flu luoromet il -N-. { 4 - [(6-nitro-7-oxo-7,8-dihydr-iridin-4-yl) -mino] -phenyl} -benzamide (50 mg) minimum to dissolve SM) / eOH (3 io Pd / C (20 mg) and the mixture was hydrogenated Example 91 uoro-N- [4- (5-hydroxy-7-oxo-7,8-dihydro- [1,8] naft ilamino) -phenyl] -2-trifluororneti-1-benzamide Example 92 (5-Hydroxy-7-oxo-7,8-dihydro- [1,8] naphthyridin-4-phenyl] -benzamide 4- (5-Cyclopropylmethoxy-7-oxo-7,8-dihydro- [1,8] naph 4-ylamino) -phenyl] benzamide Example 94 [4- (5-Methyl-7-oxo-7,8-dihydro- [1,8] naphthyridin-4-i phenyl] -benzamide Example 95 luoro-N- [4- (5-methyl-7-oxo-7,8-dihydro- [1,8] nafti ilamino) -phenyl] -2-trifluoromethyl-benzamide luoro-N- [4- (6-fluoro-7-oxo-7,8-dihydro- [1, 8] naf i ilamino) -phenyl] -2-trifluoromethyl-benzamide Example 97 Biochemical Tests of Enzyme for Activity of A There are numerous models for the identifi cation of signal transduction and detection of integral and several signal transduction pathways. For having the cell culture models of Khwaja, (1997), 16: 2783-93, and animal models tra hite et al., Oncogene, (2001),. 20: 7064-7072. tification of certain steps in the signal cascade, the interacting compounds used in order to modulate the signal (see, Stefens et al., Biochemical J., (2000), 351 compounds according to the invention ta in using as reagents for testing kinase dependent signal pathways in animal models, R. and Glenney, Jr., JR, J. Biol. Chem. 14535).

For the identification of n inhibitors available several test systems. In pity by scintillation (Sorg et al., J. of Bio ening, (2002), 7: 11-19) and plaque test call for radioactive phosphorylation of a substrate protein with ATP. In the presence of a bidor, a diminished radioactive signal, or no mourning, is detectable. Generation-resolved fluorescence resonance transfer (HTR-FRET) and fluorescence polarization technologies are suitable test methods (Sills et al olecular Screening, (2002) 191-214), as is the known calibrator test. by the experts. the enzyme by measuring the amounts of phosphorylated phosphorylated fluorescently labeled substrate at the end of an enzymatic reaction, peptide states are resolved to potential binding through the sample. The pre-charged phosphate group in the product (in opposing time) causes a different mobility of peptide peptides. This is visualized by fluorescent excitation in the substrate peptides and presented as peaks within the software of an LC3000 Method To measure the inhibitory activity of Aurora A in Caliper Life Sciences L a liquid handling instrument TTP Mosqu car 0.25 μ? of an appropriate concentration of 1 mM MgC12 (Sigma, M1028) 1 μ? of substrate peptide (sequence .SLG- ((C = 0) NH2), synthesized by Tufts Peptide ice. 100 mM of HEPES pH 7.5 (Calbiochem, 39133 -35 (Sigma, B4184) The reaction was incubated for 90 min at which time it was stopped by the addition of 70 μ? of stop H (100 mM HEPES pH 7.5, 0.015% 10 mM EDTA (Sigma, E7889)).

The plate was read in a calibrator Caliper n mobile displacement test format, by using the following parameters of 12 sorbers: sieving pressure -0.12 upstream -2700, current voltage. These conditions cause the peptide of your Desktop Profiler Method The Desktop Profiler uses the same prin C 3000 to calculate the percentage of time conversion to product. Caliper Life Sciences provided previously made, frozen, instant wells containing selected kinases. Each c plate of 384 wells contained a sellar kinase. A second plate, the plate contains a mixture of fluorescent substrate peptide and ATP. These were arranged in column transfer for the substrate plate to the ma supplied the correct enzyme with the correct concentration / ATP.

The compounds were added to a frozen plate in the desired format, in concen- trations. Reactions were initiated by transect each well per percent inhibition in positive and negative controls (without inhibitors ectively).

The results of compounds tested in these two systems are given in Table 1 below: Table 1 ost * Aurora kinase A ** Aurora ciña IC5o in nM IC50 in nM + + + + + + + + ++ + + + + + + placed * Aurora kinase A ** Aurora ciña IC50 in nM IC50 in nM + + + + + + +++ +++ ++++ ++++ ++++ ++++ + + + + ++ + + + ++++ ++++ ++++ ++++ ++++ + ++++ ++++ ++++ +++ npuesto * Aurora kinase A ** Aurora ciñ IC50 in nM IC50 in nM + + + + ++++ + ++++ + + + ++++ ++++ ++++ ++++ +++ + + + + + + + + + + + + + + + + + + Clarity of understanding purposes, it will be true for a person skilled in the art to the teachings of this invention, which can be made and modifications thereto without departing from the scope and scope of the invention.

It is noted that in relation to this method known to the applicant for carrying out said invention, it is that which results from the description of the invention.

Claims (1)

1. CLAIMS The invention having been described as ant to the property as contained in the indications: 1. A compound characterized in that it is III, IV or I: (ffl) (IV) And and W each independently is O, S, R is H, halogen, cyano, nitro, luoromethyl, heteroalkyl, OR ", SR 'and NR1 R", and R "each independently is H, genoalkyl, alkylohalogen, or heteroalkyl; or a heteroalkyl which optionally binds in emo The carbon atoms attached to the ring are attached, so that a synthetic structure is formed; Ri / R2 / R3 each independently is H, or oxidized form of sulfur; halogen, nitroyl, formyl, hydroxy, hydroxyalkyl, alkoxy oxy, carboxylic acid, an ester of carboxylic acid amide carboxylic acid such as - (C = 0) or acetic acid, acetic acid ester, acid amide includes an acid amide acetic which can independently be H, alkyl, aminalkylaminoalkyl, arylaminoalkyl, cakalkyl, or heteroaryl-aminoalkyl; and where the N atom of an aminoalkyl group is attached to the N atom to which they are attached, a ar can be a heterocyclyl group; n is 1, 2, 3 or 4, with the condition of qu = 0 when X is different from oxygen; A is a 3-7 membered ring, saturated, optionally having 1 or more heterons optionally substituted; Cy is selected from the group consisting of unsubstituted or substituted alkyl, bicyclic, heterocycle and heteroaryl; Z is H, SH, hydroxy, halogen, aminoyl, alkylamino-heterocycle, dialkylamino-het 2. The compound of conformity indication 1, characterized because it is of the form: X is NH, NH-C (= 0), (-C = 0) NH, - -0. { = 0) ?? H, CH2, -C = C-, or -HC = CH; W is O, S, CH2, or NH; R is H, halogen, cyano, nitro, luoromethyl, heteroalkyl, OR ', SR' and NR 'R ", in R "each independently is H, genoalkyl, alkylohalogen, or heteroalkyl; or heteroalkyl, which optionally binds in emo to attached carbon atoms of the ring is attached, whereby a cyclic structure is formed; Ri, 2, 31 each independently is ether or oxidized form of sulfur; halogen, nitrilaminoalkyl, dialkylaminoalkyl, alkylaminoalkoxy, alkyldiaminoalkoxy, alkoxyhexylaminoamide, carboxymacilaminoamide, hydroxyalkylhydroxy ester, ilamide ester, dihydroxyalkylamide ester, oxyalkylamide acid, wherein Rx and Ry c may be pendently H, alkyl, amino-lanylaminoalkyl, arylaminoalkyl, ca -alkyl, or heteroaryl-aminoalkyl; and where the N atom of an aminoalkyl group is attached to the N atom to which they are attached, a ar can be a heterocyclyl group; n is 1, 2, 3 or 4, with the condition that = 0 when X is different from oxygen; or a pharmaceutically acceptable salt, prodrug, hydrate, solvate, tonic, tautomer or enantiomer a to the phenyl ring to form 1,3-dioxolane; in subformula Ic, W is O, X is O, n = in subformula Id, W is S, X is CH2 / n l;. in the subformula le, W is NH, X is CH2 / n; in the If subform, W is O, X is NH, n = luoro. 4. The compound of conformity | indication l, characterized because it is of the form: X is NH, NH-C (= 0), NH-CH2 / (-C = 0) NH, H-C (02NH, CH2 / -C = C-, or -HC = CH-; Q is NH (C = Y) or < C = Y) NH; Y and W each independently is O, S, oxy, carboxylic acid, an ester of carboxylic acid caramide such as - (C = 0) - or acetic acid, acetic acid ester, acid amide includes an acid amide acetic - (C = 0) -N (RxRy), substituted aryl ituido, heterocyclic alkoxy, heterocycle or heterocycle or unsubstituted / alkylamino, dialkyalkylaminoalkyl, dialkylaminoalkyl, alkylaminoalkoxy, alkyldiaminoalkoxy, alkoxy heterylamino amide, acid ester carboxy quilaminoamide, hydroxyalkyl-hydroxy, ilamide ester, dihydroxy alkylamide ester, oxyalkylamide acid, wherein R x and R y c may be H, alkyl, aminalkylaminoalkyl, arylaminoalkyl, cakalkyl, or heteroaryl-aminoalkyl; and finally with claim 4, but in which in subformula Illa, Q is NH (C = 0), W is and A and Cy are phenyl; in subformula Illb, Q is NH (OO) xyphenyl; in the lile subformula, Q is NH (C = 0) lphenyl; in subformula Illd, Q is NH (C = 0) and Cy e luoromethylphenyl; in the lile subformula, Q is NH. { C = 0) ofhenyl or dichlorophenyl; in subformula Illf, Q is NH (C = 0) yl; in subformula Illg, Q is NH (C = 0) ornílo; in the subformula Illh, Q is NH (C ^ O) in sub-formula IIIo, Q is (C = 0) NH-ofhenyl or dichlorophenyl; in subformula IIIp, Q is (C = 0) NH ilo; in subformula Illq, Q is (C = 0) NH ornyl; in subformula I lr, Q is (C = 0) NH luoromethoxyphenyl. 6. The compound of conformity indication 1, characterized because it is of the fódede: X is NH, NH-C (= 0), NH-CH2i (-C = 0) NH, NH-C (02NH, CH2, -C = C-, O -HC = CH-; And it is O, S, O NH; A is a 3-7 membered ring, saturated, optionally having 1 or more heterethyl alkyl ketone, alkylpropanoyl, dialkyl or acetic, or acetic acid amides; Z 'is C or N; denotes the presence or absence of a RI, R2 / R3 / each independently is ter or oxidized form of sulfur; halogen, nitrile, formyl, hydroxy, hydroxyalkyl, alkoxy oxy, carboxylic acid, an ester of carbamide carboxylic acid such as - (C = 0) -N (RxRico, acetic acid ester, acide acid amide an amide of acetic acid having 0) -N (RxRy), substituted or unsubstituted aryl radical, heterocycle or substituted heteroaryl, alkylamino, dialkylamino, alkylaminocheaminoalkyl, alkyldiamino, alkylamyldiaminoalkoxy, heterocyclic alkoxy, alkylary a heterocyclyl group; or a salt, prodrug, hydrate, solvate, racemic, or pharmaceutically enantiomer. 7. The indication conformance compound 6, characterized in that the respects in greater detail have the significance with claim 6, but in which in subformula IVa, Ri is H, X is lo, Cy is phenyl, and Z is 4 - dimethylamino-piperidi in subformula IVb, Ri is H, X is lo, Cy is phenyl, and Z is dimethylamino-ethylamine; in subformula IVc, Z is dimethylamine; in subformula IVd, Z is dimethyidine; Thylaminoethylcarboxylic, * in sub-formula IV, W is O, Y is O, X is lo, Cy is difluorophenyl, and Z is droxypropylcarboxylic amide; in subformula IVk, W is O, Y is 0, X is lo, Cy is difluorophenyl, and R2 is methylacetic acid in subformula IVm, W is O, Y is O, X is lo, Cy is difluorophenyl, and R2 is oxyethylacetic amide. 8. A pharmaceutical composition comprising a compound of the formula III, an entity with claim 1, and a physiologically acceptable carrier. 9. An indication compliance composition 8, characterized in that the compound is in an amount of approximately 0.1-1000, parenteral, intradermal, intranasal, abucal, intravenous, intramuscular or iontophoretic. 13. A method for preparing a commmunity with claim 1, characterizes the steps of: to. reacting an intermediate compound V, VI or VII: (V) (VI) 0 (VII) where : B is a ring of 4-10 members, saturated, which may be mono-, bi-, or tricy or acetic; Y R and W have the same meanings given by I, II, III and IV; with t-butyl COCI in pre to provide a first intermediate product substituted with t-butylcarboxamide; b. reacting the first buffer with butyllithium in DMF to provide an intermediate uct that is an optional acetyl, pyridine substituted with t-butylcarboxyl c. reacting the second buffer with t-butyl methyl ester in the presence of providing a third intermediate product which has substituents hydroxymethyl or t-butylcarboxylic ester and t-butylcarboxamide, and further substituted; d. reflux the third product, in the presence of Pd and X-phosphate for the purpose of the final product. 14. . A method of treating a proliferative, autoimmune, inflammatory inflammation characterized in that it comprises administre that the same needs a therapeutical amount of a compound in accordance with the reivi 15. The method of conformance with the reivi characterized in that the disorder is selected consists of angiogenesis, cancers, riosclerosis, ocular disease, arthritis, osteoarthritis, glomerulonephritis, psoriasis, restenosis, rasplating, cirrhosis, viral infections and autoimmune bacteria. 16. The method of compliance with the reivi 20. A kit characterized in that it comprises rados, the first has a therapeutic amount of a pharmaceutical composition according to claim 8, and the second has a pharmaceutically effective of a pharmaceutical composition rende a pharmaceutically active ingredient ad 21. The indication conformance compound 1, characterized in that it is selected or consists of N- (4-aminophenyl) -2-fluoro-benzamido-pyrimidin-2-yl) -benzamide; N- (4-aminophenyl) -amide; N- (4-Aminophenyl) -2-trifluoromethyl-benzamido) -2-trifluoromethyl-benzamide; N- (4-amino-l luoromethyl-benzamide; N- (4-aminophenyl) -2-loromethyl-benzamide; N- (4-aminophenyl) -4-loromethyl-benzamide; N- (-aminophenyl) -2,6-amide N- (4-Aminophenyl) -3,4-difluoro-benzamide minophenyl) -2-methyl-benzamide; N- (4-aminophenyl) amide; (-aminophenyl) -oxicyl acid amide; N- (4-Aminophenyl) -2,6-dichloro-benzamide ofenyl) -3,4-dichloro-benzamide; N- (4-aminophene-gold-benzamide; N- (4-chloropyridin-2-tylpropanamide; N- (4-chloro-3-formylpyridin-2-tylpropanamide; 3- {4-chloro-tylpropanoyl) -amino] -pyridin-3- il) -3-hydroxypropane butyl, 5-chloro-l, 8-naphthyridi-2 (1H) -one, N- (4- (7-dro-1,8-naphthyridin-4-amino-amino) phenyl) -enomamide; 7, 8-dihydro-l, 8-naphthyridin-4-yl-amino) pyrimidin-2-enzyme; 2-fluoro-N- (4- (7-oxo-7-r 8-dih-iridin-4-yl-amino) phenyl) -benzamide; 3-fluoro-N- (dihydro-1, 8-naphthyridin-amyl) phenyl) benzamid ro-N- (4- (7-OXO-7,8-dihydro-1,8-naphthyridin-4-yl) -o) phenyl) benzamide; 2-trifluoromethyl-N- (4 - (7-naphthyridin-4-amino-phenyl) -benzamide; 2, 4-dif1? xo-7, 8-dihydro-l, 8-naphthyridin-4-amino-amino) phenyl) b - (7-oxo-7,8-dihydro-l, 8-naphthyridin-4-yl) phenyl) cyclohexanecarboxamide; N- (4- (7 -oxo-7,8-naphthyridin-4-yloxy) phenyl) -enoxamide; N- (2- (7 dro-1, 8-naphthyridin-4-ylamino) phenyl) benzamide; dihydro-1,8-naphthyridin-4-ylamino) -N-phenyl-benzam (trifluoromethyl) -N- (4- (7-oxo-7,8-dihydro-l, 8-naphth-phenyl) -benzamide; N-naphthalen-2-yl-4- (7-dro-1,8-naphthyridin-yl-amino) benzamide; 2 -met xo-7, 8-dihydro-l, 8-naphthyridin-4-yl-amino) phenyl) byl-N- (4- (7 -oxo-7,8-dihydro-l, 8-naphthyridin- 4 -yl- o) phenyl) benzamide; 2-fluoro-4-trifluoromethyl-N- (dihydro-1, 8-naphthyridin-4-amino-amino) phenyl) benzamid ro-5-trifluoromethyl-N- (4 - (7-oxo-7,8-dihydro- l, 8-iridin-4-yl-amino) phenyl) benzamide; 4-chloro-N- (-dichloro-N- (4- (7-oxo-7,8-dihydro-1,8-naphthyrin) phenyl) benzamide; N- (4- (7-cl) tiridin-4- il-amino) pheni 1) benzamide; N-thi-lamino-piperidin-1-yl-1,8-napht-i-di-din-4-io) -phen-1-benzamide; N- (4 - '(7 - (4-dimethylamino) -1,8-naph t-di-din-4-amino-amino) f-enyl) ben - (7 - (4-dimethyl-lamino-pro-lamino) -1,8-naph ti 1 -amino) f eni 1) benzamide; N - (4 - (7 - (4-dimethylolidin-1-yl) -1,8-napht-iri din-4-i 1-o) f-enyl) -benzamid; N- (4 - (7 - { -dimet i) -l, 8-naphthyridin-4-ylamino) phenyl) benzamido (7- (4-dimethylamino-propoxy) -1,8-napht-iridin- o) phenyl) enzyme; - (4- (7- (2-pyrrolid i) -1,8-naphthyridin-4-ylamino) phenyl) benzamido (7 - (3-morpholin-4-yl-propoxy) -1,8 -naph go i din o) f eni 1) benz amid; N- (4 - (7 - (2-morphol-1, 2-dihydro-l, 8-naphthyridine-3-carboxylic-roxy-ethyl) -amide of 5 - [(3,4-d ZOÍ-lamino)] - phenylamino] -2-oxo-4-phenyl-1,2-di-napht-iridine-3-carboxylic acid; i droxipropi 1) - 5 - [(3/4-d-Zylamino) -phenylamino] -2-oxo-4-phene-1, 1, 2-di-naphturidine-3-carboxylic acid amide; (5-chlor-dihydro-1,8-naphthyridin-3-yl) -acetic acid; cc, 4 -di-f-benzoylamino) -phenylamino] -2-oxo-l-1,2-dihydro-1, 8-naph t ir idine-3 -acetic oxy-et i 1) - 5 - [(3,4-d-oylamino) -phenylamino] -2-oxo-4-phene 1 - 1, 2-di. - naphturidine- 3-acetic, 3,4-Dif luoro- or -7-oxo-7,8-dihydro-l, 8-n-ftiridin-4-yne) phenyl) benzamide, 4-Fluoro-2-trif luoro (-nit o- 7 -oxo- 7, 8-dihydro-l, 8-naf t iridin-4 8] naf tiridin-ylamino) -fenyl] benzamide, il-7-oxo-7,8-dihydro - [1, 8] naphthyridin-4-yl] -benzamide, 4-Fluoro-N- [4- (5-methyl-7- dro - [1,8] napht-iridin-4-ylamino) -phenyl ] - 2 - luoromet i 1 -benzamide, 4-Fluoro-N- [4- (6-f -1,8-dihydro- [1,8] naphthyridin-4-ylamino) - f in luoromet i 1 -benzamide .